Adsorption of immunopotentiators to insoluble metal salts
Immunopotentiators can be adsorbed to insoluble metal salts, such as aluminum salts, to modify their pharmacokinetics, pharmacodynamics, intramuscular retention time, and/or immunostimulatory effect. Immunopotentiators are modified to introduce a moiety, such as a phosphonate group, which can mediate adsorption. These modified compounds can retain or improve their in vivo immunological activity even when delivered in an adsorbed form.
1. A TLR7 agonist of formula (D):
wherein:
P 5 is selected from H, C 1 -C 6 alkyl, and —Y-L-X—P(O)(OR X )(OR Y ); P 6 is selected from H, C 1 -C 6 alkyl each optionally substituted with 1 to 3 substituents selected from C 1 -C 4 alkyl and OH, and —Y-L-X—P(O)(OR X )(OR Y ); and P 7 is selected from H, C 1 -C 6 alkyl, —((CH 2 ) p O) q (CH 2 ) p O s —, —NHC 1 -C 6 alkyl and —Y-L-X—P(O)(OR X )(OR Y ); with the proviso that at least one of P 5 , P 6 and P 7 is —Y-L-X—P(O)(OR X )(OR Y );
R X and R Y are independently selected from H and C 1 -C 6 alkyl;
R D is selected from H and C 1 -C 6 alkyl;
X is selected from a covalent bond, O and NH;
Y is selected from a covalent bond, O, C(O), S and NH;
L is selected from, a covalent bond, C 1 -C 6 alkylene, C 1 -C 6 alkenylene, arylene, heteroarylene, C 1 -C 6 alkyleneoxy and —((CH 2 ) p O) q (CH 2 ) p — each optionally substituted with 1 to 4 substituents independently selected from halo, OH, C 1 -C 4 alkyl, —OP(O)(OH) 2 and —P(OXOH) 2 ;
each p is independently selected from 1, 2, 3, 4, 5 and 6;
q is selected from 1, 2, 3 and 4; and
s is selected from 0 and 1.
2. A composition comprising the TLR7 agonist of claim 1 and an insoluble metal salt.
3. The composition of claim 2 , wherein the TLR7 agonist is adsorbed onto the insoluble metal salt.
4. The composition of claim 3 , wherein at least 80% of the total TLR7 agonist in the composition is adsorbed onto insoluble metal salt.
5. The composition of claim 4 , wherein the adsorbed TLR7 agonist is, when injected intramuscularly, still present in the injected muscle at least 12 hours later.
6. The composition of claim 4 , wherein the adsorbed TLR7 agonist, when injected intramuscularly, has a lower peak serum concentration (Cmax) than the same TLR7 agonist when injected intramuscularly in non-adsorbed form.
7. A process for preparing an adjuvant complex, comprising a step of mixing the TLR7 agonist of claim 1 with an insoluble metal salt such that the TLR agonist interact to form the complex.
8. The process of claim 7 , further comprising (ii) sterilising the complex.
9. A process for preparing an immunogenic composition, wherein the process comprises mixing the TLR7 agonist of claim 1 , an insoluble metal salt, and an immunogen, thereby providing the immunogenic composition.
10. A composition comprising: (a) an adjuvant complex prepared by the process of claim 7 ; and (b) at least two different immunogens.
11. The composition of claim 10 , wherein the adjuvant complex comprises the TLR7 agonist adsorbed to the insoluble metal salt.
12. The composition of claim 10 , wherein the composition includes (i) a diphtheria toxoid, a tetanus toxoid, and an acellular pertussis antigen; (ii) a diphtheria toxoid, a tetanus toxoid, a pertussis antigen, and a H.influenzae type B capsular saccharide conjugate; (iii) a diphtheria toxoid, a tetanus toxoid, a pertussis antigen, and a hepatitis B virus surface antigen; (iv) a diphtheria toxoid, a tetanus toxoid, a pertussis antigen, a hepatitis B virus surface antigen and a H.influenzae type B capsular saccharide conjugate; (v) a diphtheria toxoid, a tetanus toxoid, a pertussis antigen, and an inactivated poliovirus antigen; or (vi) a diphtheria toxoid, a tetanus toxoid, a pertussis antigen, a H.influenzae type B capsular saccharide conjugate, a hepatitis B virus surface antigen, and an inactivated poliovirus antigen.
13. The composition of claim 12 , wherein the composition also includes further antigens, such as from N.meningitidis or S.pneumoniae.
14. The composition of claim 10 , wherein the composition includes at least one bacterial antigen and at least one viral antigen.